More effort needed to reduce methotrexate overdosing

Manufacturers, the TGA and health professionals need to do more to reduce the risk of potentially fatal overdosing with methotrexate, most commonly from taking the drug daily rather than weekly, an Australian study has concluded.

Dr Rose Cairns, from the NSW Poisons Information Centre, and colleagues identified 22 methotrexate-associated deaths in coroners’ cases nationwide between 2000 and 2014, of which seven had accidentally taken the drug for at least three consecutive days.

There were also 10 cases of medication error reported to the TGA’s adverse events notification system between 2004 and 2015, of which two were fatal. Australia’s four poison information centres, in Brisbane, Sydney, Melbourne and Perth, included 92 cases during the same period. There was little overlap between the cases.

“Dosing errors with methotrexate can be lethal and continue to occur despite a number of safety initiatives in the past decade,” they wrote in the Medical Journal of Australia. “Further strategies to reduce these preventable harms need to be implemented and evaluated.”

Most methotrexate is dispensed as packs of 50 x 10 mg tablets, more than a year’s supply for some patients. The recommended dose as an immunomodulator in conditions such as rheumatoid arthritis, psoriasis and inflammatory bowel disease is 7.5 to 25 mg/week.

Prescribing of this formulation continued to increase throughout the study period, despite it being listed as a restricted benefit in 2008 and a 15 x 10 mg pack being introduced.

Possible steps to reduce the risks included further reductions in the pack size, packaging folate and methotrexate together to reduce confusion of the two drugs, and formulating methotrexate tablets as a distinctive colour (both it and folate are small yellow tablets).

“Further packaging changes could be made, including clear labelling of the box with a statement such as ‘Warning: this medicine is usually taken weekly. It can be harmful if taken daily’,” Dr Cairns and colleagues said.

“Similar labelling changes have been recommended in Australia and elsewhere, and the results of this study suggest that more needs to be done to mandate…the companies supplying methotrexate in Australia to enact these changes.”

Reasons for errors in the fatal cases reviewed by coroners included dosette packaging errors by pharmacists (three cases), prescribing error (one), mistaking methotrexate for another medication (one), dosing error by carer (one), and prescriber-patient miscommunication (one).

Similar problems were reported in cases managed by poisons information centres: mistaking methotrexate for folic acid or prednisone was a common problem.

All seven patients in the coroners’ database who died after documented dosing errors had abnormal blood counts and had taken methotrexate for between three and 10 consecutive days.

Causes of death in patients taking the drug but without a documented dosing error included alveolar damage or pulmonary fibrosis, pneumonia, sepsis, pancytopenia, chronic liver disease and gastrointestinal haemorrhage.

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